Researchers identify genes in fruitflies that may shed light on human cancer spread

By searching through all the genes in the fruitfly genome, Johns Hopkins scientists have identified those required for a certain type of cell migration and simultaneously captured a global view of all the genes turned on when cells are on the move.

The study, to be published April 3 in Developmental Cell, has implications for understanding cell migration and perhaps controlling cancer cells that move similarly to spread beyond an original tumor, which are what eventually kills most cancer patients.

The research identified several hundred genes that are preferentially turned on in so-called border cells of the fruitfly ovary that migrate during normal development. Two main types of genes came out of this search: those known to be involved in maintaining cell shape and structure and which become very dynamic in migrating cells; and a group of genes involved in transporting materials from the inside of a cell to its membrane surface and back again.

"So-called border cell migration shares common characteristics with metastatic cancer cells," says Xuejiao Wang, M.D., Ph.D., the first author of the study and a postdoctoral fellow in the Department of Biological Chemistry. "Cells must detach from where they are, migrate between other cells and tissues, and travel to a final destination."

Although border cell migration in the fruitfly ovary may seem a far stretch for studying human cancer metastasis, the genes uncovered in this study share more similarities with those that arise from studies of human metastatic breast cancer cells than they do with studies of other tissues in the fruitfly, according to the study's senior author, Denise Montell, Ph.D., a professor in the Department of Biological Chemistry.

The 353 genes identified in this study include some that are known to play a role in both border cell migration in fruitflies and metastasis in animal cancer cells; some that had long been suspected to play a role in cell migration, but have been more difficult to study

because their functions are shared by other genes; and some that are well understood for their roles in other cellular functions but without this study would not have been obvious candidate genes in cell migration. The results help these researchers as well as others in the field by pointing out genes to study further.

"This really was a hypothesis-generating experiment," says Montell. "The results of this study tell us where to focus future efforts."

Understanding the genetic mechanisms underlying cell migration is critical for understanding normal development, and inflammation, as well as metastasis. Classical genetic approaches for identifying key genes – mutational analysis, for example – have been successful but generally yield information about genes with unique functions only, and only one gene at a time. Whole genome studies, like the microarray analysis used in this study, allow researchers to identify genes that share similar functions in a way that mutational analysis cannot. And, whole genome approaches can look at most of the genes in the genome at one time.

As part of their previous work, Montell's group had generated mutant flies that show defects in border cell migration. This study identified five of the genes mutated in those flies and gives the researchers a starting point for more detailed analysis of how those genes are involved in cell migration. Wang has begun to study some of these genes to further dissect their function. The researchers also hope to perform more whole genome analyses to identify genes that interact with those already known to play a role in cell migration and metastasis.

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The researchers were funded by the Cell Migration Consortium.

Authors on the paper are Wang, Jinyan Bo, Tina Bridges and Montell, all of Hopkins, and Katherine Dugan, Tien-chi Pan and Lewis Chodosh of the Abramson Family Cancer Research Institute at the University of Pennsylvania School of Medicine.